Cannabis use disorders are a significant public health concern that disproportionately affect youth. Although promising psychosocial interventions are being developed, most youth do not benefit from these interventions alone. In light of the clinical demand for improved treatments for youth, NIDA recently identified the critical need for data on the tolerability and potential efficacy of medications in adolescents (RFA-DA-09- 001). The major objective of this application is to test whether topiramate (TPM), an anticonvulsant medication under intense study for treating several drugs of abuse, affects cannabis use and related phenotypes in youth. TPM facilitates gamma aminobutyric acid (GABA) neurotransmission and blocks AMPA/kainite glutamate receptors. Because mesocorticolimbic dopamine (DA) release, which contributes to the rewarding effects of acute drug use, is under tonic inhibitory control via GABAergic neurons and excitatory control via glutamatergic neurons, TPM's concurrent GABAergic agonism and glutamatergic antagonism is thought to reduce drug use, in part, by attenuating craving. Indeed, TPM reduces alcohol, nicotine, and cocaine use. Although the effects of TPM on cannabis abuse are untested, cannabis exerts its reinforcing effects by activating the same mesolimbic DA pathways as most abused drugs and therefore is also likely to be influenced by TPM. We propose to randomize nontreatment seeking youth (n = 132;ages 15-18) with cannabis abuse or dependence to TPM (200 mg/day) or placebo for 6 weeks. Youth will monitor their cannabis use, craving, acute subjective effects of smoked cannabis, and withdrawal symptoms for the 6-week period using handheld electronic diaries. In addition, participants will complete a laboratory assessment of reactivity to cannabis-related cues. This comprehensive yet efficient analysis will provide much needed data on the effects of TPM on cannabis use in adolescents while adding important new information about the biobehavioral mechanisms of TPM action on cannabis use. PUBLIC HEALTH RELEVANCE: This study will help to determine whether the medication, topiramate, reduces cannabis use among adolescents with cannabis abuse or dependence. It also will help answer the question, "How does topiramate reduce cannabis use?" Understanding how topiramate may reduce cannabis use among adolescents would allow for a more targeted pharmacotherapeutic approach to treatment and help to identify additional medications that may hold promise for improving cannabis treatment outcomes for youth.